Pan Xinxin, Guo Chengxiao, Wang Baoli, Cao Biyun, Wu Juan, Chen Xinyu, He Shufang, Zhang Ye, Jin Shiyun
From the Department of Anesthesiology, the Second Affiliated Hospital of Anhui Medical University, Hefei, China.
Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, China.
Anesth Analg. 2025 Oct 1;141(4):706-717. doi: 10.1213/ANE.0000000000007290. Epub 2024 Nov 13.
Failing heart is more likely to suffer from myocardial ischemia/reperfusion (I/R) injury. This poses a great challenge for anesthesiologists in managing patients with heart failure during major surgery. Evidence from animal studies suggests that the delta-opioid receptor (DOR) contributes to alleviating acute myocardial injuries. However, little is known regarding the cardioprotective effects of cardiac DOR in patients with chronic heart failure. This study aimed to examine DOR expression in failing hearts and explore how DOR regulates the Janus kinase signal transducer and activator of the transcription-3 (JAK/STAT3) pathway to mediate morphine-induced cardio protection in heart failure.
We measured the DOR protein levels in human and rat heart tissues with chronic heart failure. To investigate the cardioprotective role of DOR, we administered the DOR-specific antagonist, naltrindole (NTD), and JAK2 inhibitor, AG490, before morphine preconditioning (MPC) in an isolated perfusion model of myocardial I/R injury in postinfarcted failing rat heart. We examined the infarct size, cardiac enzymes, cardiac function, cardiomyocyte apoptosis, apoptosis-related proteins, and STAT3 phosphorylation in the heart.
The protein levels of DOR were significantly elevated in the myocardial tissues of humans and rats with chronic heart failure, by 1.4-fold (mean difference 0.41; 95% confidence interval [CI], 0.04-0.78; P = .032) and 2.3-fold (mean difference 1.26; 95% CI, 0.25-2.28; P = .009), respectively, compared to control tissues. Disease severity positively correlated with DOR expression (human: R2 = 0.316, P = .004; rat: R2 = 0.871, P = .021). Blocking DOR substantially reversed the cardioprotective effects of MPC in postinfarcted rat hearts, increasing the mean (standard deviation) percentage of infarct size from 15.0 (3.9)% to 30.8 (7.7)% (P < .001). Similarly, AG490 inhibited MPC restoration of cardiomyocyte apoptosis (33.3 [4.2]% vs 16.6 [3.4]%; P < .001). Both NTD and AG490 markedly suppressed STAT3 phosphorylation by 60.1% (mean difference 0.60; 95% CI, 0.27-0.93; P = .002) and 44.1% (mean difference 0.44; 95% CI, 0.06-0.83; P = .027), respectively, and also lowered the Bcl-2/Bax ratio by 85.5% (mean difference 0.86; 95% CI, 0.28-1.43; P = .006) and 68.2% (mean difference 0.68; 95% CI, 0.51-0.85; P < .001) respectively in heart tissues at the end of reperfusion.
DOR protein levels increased in failing hearts of both humans and rats. Blocking cardiac DOR selectively reduced morphine-induced cardio protection by inhibiting the JAK2/STAT3 pathway. These findings indicate that cardiac DOR is a potential therapeutic target for protecting against heart failure due to I/R injury.
衰竭心脏更容易遭受心肌缺血/再灌注（I/R）损伤。这给麻醉医生在重大手术中管理心力衰竭患者带来了巨大挑战。动物研究证据表明，δ-阿片受体（DOR）有助于减轻急性心肌损伤。然而，关于慢性心力衰竭患者心脏DOR的心脏保护作用知之甚少。本研究旨在检测衰竭心脏中DOR的表达，并探讨DOR如何调节Janus激酶信号转导子和转录激活子3（JAK/STAT3）通路，以介导吗啡诱导的心力衰竭心脏保护作用。
我们检测了慢性心力衰竭患者和大鼠心脏组织中DOR蛋白水平。为了研究DOR的心脏保护作用，我们在梗死性衰竭大鼠心脏的离体心肌I/R损伤灌注模型中，在吗啡预处理（MPC）前给予DOR特异性拮抗剂纳曲吲哚（NTD）和JAK2抑制剂AG490。我们检测了心脏的梗死面积、心肌酶、心功能、心肌细胞凋亡、凋亡相关蛋白以及STAT3磷酸化水平。
与对照组织相比，慢性心力衰竭患者和大鼠心肌组织中DOR蛋白水平显著升高，分别升高了1.4倍（平均差异0.41；95%置信区间[CI]，0.04 - 0.78；P = .032）和2.3倍（平均差异1.26；95% CI，0.25 - 2.28；P = .009）。疾病严重程度与DOR表达呈正相关（人类：R2 = 0.316，P = .004；大鼠：R2 = 0.871, P = .021）。阻断DOR可显著逆转MPC对梗死大鼠心脏的心脏保护作用，使梗死面积的平均（标准差）百分比从15.0（3.9）%增加到30.8（7.7）%（P < .001）。同样，AG490抑制了MPC对心肌细胞凋亡的恢复作用（33.3 [4.2]%对16.6 [3.4]%；P < .001）。NTD和AG490均显著抑制STAT3磷酸化，分别抑制了60.1%（平均差异0.60；95% CI，0.27 - 0.93；P = .002）和44.1%（平均差异0.44；95% CI，0.06 - 0.83；P = .027），并且在再灌注结束时，心脏组织中Bcl-2/Bax比值分别降低了85.5%（平均差异0.86；95% CI，0.28 - 1.43；P = .006）和68.2%（平均差异0.68；95% CI，0.51 - 0.85；P < .001）。
人类和大鼠衰竭心脏中DOR蛋白水平均升高。阻断心脏DOR通过抑制JAK2/STAT3通路选择性降低了吗啡诱导的心脏保护作用。这些发现表明，心脏DOR是预防I/R损伤所致心力衰竭的潜在治疗靶点。
